Synthesis of complex, biologically active molecules is critical for the discovery and development of potential pharmaceutical agents. Multicomponent coupling reactions (MCRs) are “one-pot reactions” that combine three or more compounds simultaneously to generate highly structured products. Chemical libraries can be generated through modification of substituents to produce a set of structurally related molecules. One useful MCR, the Ugi-Smiles reaction, is a four component coupling (4CC), in which an amine, phenol, aldehyde, and isocyanide are combined to prepare a peptide-like amide structure. Previous efforts have led to the development of a tandem Ugi-Smiles intramolecular Diels-Alder (US-IMDA) process.

This work describes efforts towards variation of the US-IMDA by switching the roles of the aldehyde and amine, as diene and dienophile components, in the tandem Diels-Alder reaction. Role-reversal along with incorporation of an α,β-unsaturated aldehyde provided an unexpected Ugi-Smiles modification, a five-component coupling reaction. Evaluation of reaction conditions, the role of the solvent as the fifth component, and reaction progress have provided insight into the scope and reaction pathway for this observed Oxy-Michael Ugi-Smiles reaction.